Page 61 - Haematologica Vol. 110 - January 2025

ARTICLE - IVIG prophylaxis in pediatric ALL
K.A. Thus et al.
A recent retrospective study in pediatric patients with ALL during maintenance therapy, with a small number of patients (63 patients receiving some IgG monitoring/sup- plementation), did not show a significant impact of IVIG supplementation on febrile episodes.11 These data are hard to compare to our study, due to the retrospective character and the small size of that study.
IVIG prophylaxis likely prevented viral infections in our cohort of patients. There was no difference in the num- ber of positive blood cultures, but there was a significant decrease in admissions for fever with a negative blood culture in the IVIG prophylaxis group. Most admissions for fever with a negative blood culture were attributed to fever of unknown origin and upper respiratory tract infections, indicative of a reduction in viral infections by IVIG prophy- laxis, in line with previous observations in adult patients with lymphoproliferative diseases.9
IVIG prophylaxis was well tolerated and not associated with severe side effects, in line with previous observations,12 al- though there was a trend for more severe adverse events in the IVIG prophylaxis group. The study was not set up to analyze specific severe adverse events separately; how- ever, IVIG prophylaxis was significantly associated with an increased risk of thrombosis. The causal mechanism of thrombosis is difficult to define as, for example, patients also received asparaginase and glucocorticoids, and had central venous catheters (of note, in the DCOG ALL-11 pro- tocol patients received vincristine and dexamethasone puls- es throughout maintenance). In our country, it is common practice for patients to keep their central venous catheter throughout maintenance treatment. Our data did not include information on other risk factors for thrombosis such as factor V Leiden and activated protein C resistance. Ten out of 16 (62.5%) thromboses occurred prior to maintenance treatment, suggesting that other risk factors played a role in the development of thrombosis. Potentially, awareness of thrombosis was biased towards the IVIG group. Nonetheless, thrombosis is a potential side effect of IVIG, which should be kept in mind when prescribing IVIG prophylaxis.
It is worth noting that 15 (17%) patients in the control group received one or more IVIG infusions (under strict conditions). The control group was, therefore, formed of patients receiving standard of care and the effect of IVIG prophylaxis might have been more pronounced had the group receiving the intervention been compared against a true control group of patients who did not receive any IVIG.
The fact that the study was not blinded may theoretically have led to a bias in admitting patients in the control group to hospital more often. However, the majority of admissions were for fever in neutropenia, which is a strict indication for admission. In addition, there was no difference in duration of admission for fever between the two groups, suggesting that once admitted, patients were equally ill in both groups. We, therefore, believe that this potential bias due to non- blinding has not influenced our data considerably.
A drawback of our study is that it was designed with a ran- domization early within the DCOG ALL-11 protocol, before a large number of patients had developed hypogamma- globulinemia. In our study, only seven (4%) patients had IgG levels <4 g/L before the start of the IVIG trial, which is a commonly used cutoff for supplementation.13 Based on these seven patients, we cannot determine whether patients with hypogammaglobulinemia at diagnosis would benefit most from IVIG prophylaxis. However, in this trial, IVIG pro- phylaxis prevented admissions for fever specifically during maintenance treatment, which is also the period of lowest IgG levels (Figure 2).5 Potentially, measuring IgG levels during maintenance treatment could be helpful in determining which patients would benefit from IVIG prophylaxis.
The medium-risk group of the DCOG ALL-11 study is the largest risk group and included 70% of all patients. Only medium-risk patients were included in our IVIG prophylaxis subtrial. Although a downside of our study is that almost half of the eligible patients did not consent to the trial, we believe the data are generalizable to the entire medium-risk group, as overall and disease-free survival rates are compa- rable.3 The advantage of only including medium-risk patients in the study is that this resulted in a homogeneous group of patients in whom the effect of IVIG prophylaxis could be well studied. A limitation, however, is that this is not a subset of patients with the highest risk of (viral) infections. Ultimately, it would be useful to determine whether IVIG prophylaxis can prevent infections in patients with a high viral infection risk, for example younger patients, patients with trisomy 21, patients within families with young children, patients with an intensive (high-risk) treatment schedule, treatment during winter months and patients who have developed multiple infections previously. Moreover, it would be interesting to study the effect of IVIG prophylaxis in patients receiving newer, more targeted B-ALL therapies resulting in B-cell aplasia and consequently hypogammaglobulinemia, such as chimeric antigen receptor T cells and blinatumomab. Setting up a study only randomizing these patients with a high risk of viral infections would, however, require an extremely long recruitment period.
To conclude, in pediatric patients with medium-risk ALL, IVIG prophylaxis leads to a significant reduction of admis- sions for fever with negative blood cultures during main- tenance treatment, and leads to a decrease in the use of empirical antibiotic therapy and chemotherapy adaptations. As IVIG prophylaxis likely prevents viral infections, our data do not support routine use of IVIG prophylaxis for every ALL patient. However, a subset of patients with a high risk of viral infections might benefit from IVIG prophylaxis, with fewer admissions for fever, in maintenance treatment. When prescribing IVIG prophylaxis, clinicians should bear in mind a potential risk of thrombosis.
Disclosures
CMZ has received institutional support for clinical trials
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